Bisphosphonates and the prevention of metastasis

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Abstract
Bisphosphonates have been used successfully for many years in the treatment of hypercalcemia and to reduce skeletal-related complications of metastases. In the first years of bisphosphonate use, the efficacy of these substances was thought to lie purely in the inhibition of osteoclasts. However, there is recent evidence to suggest that an antitumor effect also may play a role. As well as having an apoptotic and antiproliferative effect on osteoclasts, bisphosphonates may exert a similar influence on macrophages and tumor cells. The current investigation summarizes all results published to date that deal with the potential antitumor properties of the bisphosphonates. On the one hand, these include results from basic research into the action mechanism and preventative models in animals. In addition, the results of initial clinical experience with metastasis prophylaxis with bisphosphonates in breast carcinoma patients are presented and interpreted. Improvements in the survival time of certain subpopulations have been found in many Phase III studies with bisphosphonates to date, both in the setting of metastatic breast carcinoma and in multiple myeloma. Some preclinical studies showed that down-regulation of bone metabolism by bisphosphonates is associated with a lower incidence of bone metastases and destruction in animals, whereas activation is correlated with a higher number of metastases. However, varying results were found in animal experiments with regard to the effect of bisphosphonates on the incidence and growth pattern of nonosseous metastases. The results of three randomized studies in patients with primary breast carcinoma in which patients received 1600 mg clodronate orally have now been evaluated and presented. All three studies arrived at different results. Because the dose was identical in all three studies, the differing results can only be either random or methodologic (inclusion criteria, sample size, etc.). Overall, the results are very promising but need confirmation in further studies. At the moment, we have more open than answered questions. First, it is unclear whether this type of adjuvant therapy with bisphosphonates should be given continually by the oral route, or whether an intravenous interval therapy could produce the same results. It is also uncertain whether the doses used in a palliative setting are optimal or whether lower doses might also suffice. The optimum period of adjuvant treatment is also subject to debate. What is clear, however, is that confirmation of the initial clinical results will open a new chapter in the treatment of malignant tumors.

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